Connective tissue diseases

Connective tissue is an important biological tissue composed of an extracellular matrix that binds, anchors, and supports organs. There are various types of connective tissue, all of which consist of varying combinations of fibers, cells, and intercellular substance. Over 200 conditions, which may be inherited or autoimmune, affect connective tissue, and they are collectively known as connective tissue diseases (CTDs). Inherited CTDs are caused by mutations that affect one of the two fibers (collagen and fibrillin). Autoimmune CTDs have no clear etiology, but the incidence is higher in women and among genetically predisposed individuals. As the name suggests, in autoimmune CTDs, the immune system develops antibodies against components of connective tissue. Individual conditions can affect a vast range of bodily structures (including cartilage, blood vessels, bone, tendons, and organs) and thus present with a wide array of clinical findings.

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Inflammatory myopathies (e.g., polymyositis; , dermatomyositis)
• Systemic sclerosis
• Sjögren's syndrome
• Mixed connective tissue disease (Sharp's syndrome)

• Ehlers-Danlos syndrome
• Marfan syndrome
• Osteogenesis imperfecta
• Alport syndrome
• Loeys-Dietz syndrome ^[1]
  • Autosomal dominant inheritance
  • Features shared with Marfan syndrome: marfanoid habitus, increased risk of ascending aortic aneurysms and aortic dissection
  • Distinct features: hypertelorism, bifid uvula, cleft palate, easy bruising and keloids, arterial tortuosity (winding course of arteries)

References:^[2][3][4][5]

Clinical features vary greatly among individual diseases. The table below provides a general overview of the more common features.

	Autoimmune CTDs	Inherited CTDs
General features	Fever, weight loss, fatigue	Fatigue, weakness
Musculoskeletal symptoms	Polyarthritis, myositis	Joint hypermobility, curved spine, brittle bones, bone deformities, growth abnormalities (short or tall stature)
Skin manifestations	Erythema, Raynaud's phenomenon	Hyperextensive, fragile skin
Organ manifestations	Heart: pericarditis Lungs: scarring (pulmonary fibrosis), pleurisy Kidneys: nephritis (e.g., glomerulonephritis) CNS: depressive moods	Heart: valve weakness/prolapse Lungs: weakness, difficulty breathing, tendency to develop emphysema Blood vessels: aneurysms, ruptures Eye abnormalities

References:^[2][3][4][5]

This table lists the most important connective tissue disorders and some examples of their clinical features. For more information on Marfan syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta, see the respective learning cards.

Condition	Etiology	Pathophysiology	Clinical features (examples)
Marfan syndrome	Autosomal dominant disease caused by mutation of fibrillin-1 gene (FBN1) on chromosome 15	Defective fibrillin → defective elastin → defective connective tissue throughout the body	Tall stature with disproportionately long extremities; joint hypermobility Arachnodactyly Aortic aneurysm and dissection Lens subluxation superiorly and temporally Heart valve defects (mitral valve prolapse) Skin hyperelasticity
Ehlers-Danlos syndrome	Heterogeneous group of six connective tissue disorders with variable inheritance (autosomal recessive or dominant) Mutation in genes controlling synthesis of collagen Classic type: mutations in COL5A1, COL5A2 → type V collagen defect Vascular type: type III procollagen defect	Defective collagen cross-linking and fibril synthesis	Varying degrees of Joint hypermobility (most common) Skin hyperextensibility Heart valve defects (particularly mitral valve prolapse) Aneurysms/dissections of the iliac, splenic, renal arteries, or the aorta
Menkes disease	X-linked recessive neurodegenerative disease caused by a mutation in the gene ATP7A (coding for Menkes protein, copper-transporting ATPase 1)	Defect in copper-transporting ATPase 1 → impaired copper absorption and transport → reduced activity of copper-dependent enzymes (e.g., lysyl oxidase, tyrosinase) → defective collagen cross-linking and fibril synthesis	Sparse, kinky hair Hypopigmented skin and hair Failure to thrive Developmental retardation Epilepsy Hypotonia Low copper and ceruloplasmin levels
Osteogenesis imperfecta	Rare, autosomal dominant inherited bone disorder due to mutation in COL1A1 or COL1A2 genes	Mutation in type I collagen gene → decreased synthesis of type 1 collagen	Brittle bones and frequent and/or multiple fractures from minimal trauma Growth retardation Skeletal deformities Blue sclera Progressive hearing loss (due to abnormal ossicles)
Scurvy	Vitamin C deficiency	Defect in hydroxylation of proline and lysine residues in procollagen → production of abnormal collagen with decreased tensile strength	Swollen gums Mucosal bleeding Poor wound healing Curly body hair Follicular hyperkeratosis Hemarthrosis Generalized weakness/fatigue

The ATP7A gene is defective in Menkes disease, whereas the ATP7B gene is defective in Wilson's disease!

Ehlers-Danlos syndrome and Menkes disease are both associated with reduced lysyl oxidase activity, resulting in defective collagen cross-linking and fibril synthesis.

References:^[6][7]